Compositions that enhance iron absorption and methods of use thereof

Abstract

Amino acid compositions useful for increasing the amount of the divalent metal-ion transporter 1, DMT1 (encoded by the gene SLC11A2), on the duodenal bmsh border membrane (BBM) are described herein. Methods for increasing the concentration of DMT1 on the duodenal BBM (on trafficking) and increasing iron uptake are also presented. Compositions and methods described herein are useful for treating a disorder or disease associated with iron deficiency in subjects afflicted with such disorders or diseases. Use of these compositions for the treatment of disorders or diseases associated with iron deficiency and in the preparation of a medicament for the treatment of disorders or diseases associated with iron deficiency are also encompassed herein.

1 . A pharmaceutical formulation for use in treating a disease or disorder associated with iron deficiency in a subject in need thereof,
 wherein the pharmaceutical formulation comprises:   a) pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least two free amino acids selected from a group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine,   wherein the therapeutically effective amount of each of the at least two free amino acids is sufficient to treat the disease or disorder associated with iron deficiency in the subject; and   b) at least one a pharmaceutically inactive ingredient.   
     
     
         2 . A pharmaceutical formulation for use in treating a disease or disorder associated with iron deficiency,
 wherein the pharmaceutical formulation comprises:   a) pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least two free amino acids selected from a first group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine,   wherein the therapeutically effective amount of each of the at least two free amino acids is sufficient to treat the disease or disorder associated with iron deficiency in the subject;   b) at least one a pharmaceutically inactive ingredient; and   c) optionally further comprising pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least one free amino acid selected from a second group of amino acids consisting essentially of cysteine, histidine, and isoleucine,   sufficient to treat the disease or disorder associated with iron deficiency in the subject.   
     
     
         3 . The pharmaceutical formulation of  claim 1  or  claim 2 , wherein each of the amino acids is an L-amino acid. 
     
     
         4 . The pharmaceutical formulation of any one of  claims 1  to  3 , wherein the pharmaceutical formulation further comprises water as a pharmaceutically inactive ingredient. 
     
     
         5 . The pharmaceutical formulation of any one of  claims 1  to  4 , wherein the at least one pharmaceutically inactive ingredient comprises a pharmaceutically acceptable carrier, buffer, electrolyte, adjuvant, or excipient. 
     
     
         6 . The pharmaceutical formulation of any one of  claims 1  to  5 , wherein the pharmaceutical formulation is sterile. 
     
     
         7 . The pharmaceutical formulation of any one of  claims 1  to  6 , wherein the pharmaceutical formulation is formulated for administration by an enteral, pulmonary, inhalation, intranasal, or sublingual route. 
     
     
         8 . The pharmaceutical formulation of any one of  claims 1  to  7 , for use as a medicament for the treatment of a disease or disorder associated with iron deficiency. 
     
     
         9 . The pharmaceutical formulation of any one of  claims 1  to  8 ,
 wherein the pharmaceutically active ingredients consist essentially of or consist of the therapeutically effective amount of each of the at least two free amino acids selected from the group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine; or 
 the pharmaceutically active ingredients consist essentially of or consist of the therapeutically effective amount of each of the at least two free amino acids selected from the the first group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine and, when present, the therapeutically effective amount of each of the at least one free amino acids selected from the second group of amino acids consisting essentially of cysteine, histidine, and isoleucine. 
 
     
     
         10 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, glutamine, and glycine. 
     
     
         11 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glutamic acid. 
     
     
         12 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, and glutamine. 
     
     
         13 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glutamine. 
     
     
         14 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamine, and glycine. 
     
     
         15 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glycine. 
     
     
         16 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid and glutamine. 
     
     
         17 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid, glutamine, and glycine. 
     
     
         18 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid and glycine. 
     
     
         19 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of glutamine and glycine. 
     
     
         20 . The pharmaceutical formulation of any one of  claims 1  to  9 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, and glycine. 
     
     
         21 . The pharmaceutical formulation of any one of  claims 1 - 20 , wherein a concentration of each of the amino acids present ranges from 0.1 mM to 12 mM or 0.5 mM to 12 mM. 
     
     
         22 . The pharmaceutical formulation of any one of  claims 1 - 21 , wherein, when included, a concentration of valine is 10 mM, a concentration of threonine is 8 mM, a concentration of tyrosine is 1.2 mM, a concentration of serine is 10 mM, and a concentration of lysine is 4 mM. 
     
     
         23 . The pharmaceutical formulation of any one of  claims 1 - 22 , wherein the pH ranges from 5.5 to 8.0 or is about 6.5. 
     
     
         24 . The pharmaceutical formulation of any one of  claims 1 - 23 , wherein the disease or disorder associated with iron deficiency comprises iron-deficiency anemia (IDA); anemia associated with chronic kidney disease; iron-refractory, iron-deficiency anemia (IRIDA); anemia associated with inflammation; anemia associated with pregnancy; anemia associated with excessive menstrual blood loss; anemia associated with dietary iron insufficiency; anemia associated with intestinal infections, or anemia associated with inflammatory bowel diseases. 
     
     
         25 . The pharmaceutical formulation of  claim 24 , wherein the anemia comprises iron-deficiency anemia (IDA). 
     
     
         26 . A method for treating a disease or disorder associated with iron deficiency in a subject in need thereof, the method comprising:
 administering a pharmaceutical composition to the subject in need thereof,   wherein the pharmaceutical composition comprises:   a) pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least two free amino acids selected from a group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine, wherein the therapeutically effective amount of each of the at least two free amino acids is sufficient to treat the disease or disorder associated with iron deficiency in the subject; and   b) at least one a pharmaceutically inactive ingredient.   
     
     
         27 . A method for treating a disease or disorder associated with iron deficiency in a subject in need thereof, the method comprising:
 administering a pharmaceutical composition to the subject in need thereof,   wherein the pharmaceutical composition comprises:   a) pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least two free amino acids selected from a first group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine,   wherein the therapeutically effective amount of each of the at least two free amino acids is sufficient to treat the disease or disorder associated with iron deficiency in the subject;   b) at least one a pharmaceutically inactive ingredient; and   c) optionally further comprising pharmaceutically active ingredients comprising, consisting essentially of, or consisting of a therapeutically effective amount of each of at least one free amino acid selected from a second group of amino acids consisting essentially of cysteine, histidine, and isoleucine,   wherein the therapeutically effective amount of each of the at least one free amino acids is sufficient to treat the disease or disorder associated with iron deficiency in the subject.   
     
     
         28 . The method of  claim 26  or  claim 27 , wherein each of the amino acids is an L-amino acid. 
     
     
         29 . The method of any one of  claims 26 - 28 , wherein the pharmaceutical formulation further comprises water as a pharmaceutically inactive ingredient. 
     
     
         30 . The method of any one of  claims 26 - 29 , wherein the at least one pharmaceutically inactive ingredient comprises a pharmaceutically acceptable carrier, buffer, electrolyte, adjuvant, or excipient. 
     
     
         31 . The method of any one of  claims 26 - 30 , wherein the pharmaceutical formulation is sterile. 
     
     
         32 . The method of any one of  claims 26 - 31 , wherein the pharmaceutical formulation is formulated for administration by an enteral, pulmonary, inhalation, intranasal, or sublingual route. 
     
     
         33 . The method of any one of  claims 26 - 32 , wherein
 the pharmaceutically active ingredients consist essentially of or consist of the therapeutically effective amount of each of the at least two free amino acids selected from the group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine; or   the pharmaceutically active ingredients consist essentially of or consist of the therapeutically effective amount of each of the at least two free amino acids selected from the first group of amino acids consisting essentially of aspartic acid, glutamic acid, glutamine, and glycine and, when present, the therapeutically effective amount of each of the at least one free amino acids selected from the second group of amino acids consisting essentially of cysteine, histidine, and isoleucine.   
     
     
         34 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, glutamine, and glycine. 
     
     
         35 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glutamic acid. 
     
     
         36 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, and glutamine. 
     
     
         37 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glutamine. 
     
     
         38 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamine, and glycine. 
     
     
         39 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid and glycine. 
     
     
         40 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid and glutamine. 
     
     
         41 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid, glutamine, and glycine. 
     
     
         42 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of glutamic acid and glycine. 
     
     
         43 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of glutamine and glycine. 
     
     
         44 . The method of any one of  claims 26 - 33 , wherein the at least two free amino acids consist essentially of or consist of aspartic acid, glutamic acid, and glycine. 
     
     
         45 . The method of any one of  claims 26 - 44 , wherein a concentration of each of the amino acids present ranges from 0.1 mM to 12 mM or 0.5 mM to 12 mM. 
     
     
         46 . The method of any one of  claims 26 - 45 , wherein, when included, a concentration of valine is 10 mM, a concentration of threonine is 8 mM, a concentration of tyrosine is 1.2 mM, a concentration of serine is 10 mM, and a concentration of lysine is 4 mM. 
     
     
         47 . The method of any one of  claims 26 - 46 , wherein the pH of the pharmaceutical composition ranges from 5.5 to 8.0. 
     
     
         48 . The method of any one of  claims 26 - 47 , wherein the pH is about 6.5. 
     
     
         49 . The method of any one of  claims 26 - 48 , wherein the disease or disorder associated with iron deficiency comprises iron-deficiency anemia (IDA); anemia associated with chronic kidney disease; iron-refractory, iron-deficiency anemia (IRIDA); anemia associated with inflammation; anemia associated with pregnancy; anemia associated with excessive menstrual blood loss; anemia associated with dietary iron insufficiency; anemia associated with intestinal infections, or anemia associated with inflammatory bowel diseases. 
     
     
         50 . The pharmaceutical formulation of  claim 49 , wherein the anemia comprises iron-deficiency anemia (IDA).